Cancer has become the worldwide deadliest disease, and the proportion of deaths from cancers is very high in developed countries. Cancer can occur in a variety of organs and tissues at any age, and the main types of cancer leading to the death are: lung cancer, stomach cancer, liver cancer, colon cancer, breast cancer, and so on. In recent years, lung cancer has become the highest incidence rate of malignant tumors. According to World Health Organization (WHO) statistics, 1,600,000 people were diagnosed with lung cancer all over the word in 2008, accounting for 13% of the total cancer incidence, and 1,400,000 deaths, accounting for 18% of all cancer deaths (Jemal A, et al. C A Cancer J. Clin. 2011, 61: 69-90); in 2010, a total of 222,520 new lung cancer cases and 157,330 cancer deaths occurred in the United States, who died from non-small cell lung cancer (NSCLC), accounting for 85% of all cases of lung cancer (Jemal A, et al. C A Cancer J. Clin. 2010, 60: 277-300). In recent years, among the top 10 malignant tumors in China's urban and rural areas, lung cancer has replaced liver cancer and ranked as the first leading cause of mortality among people with malignant tumors in China, accounting for 22.7% of all malignant tumor deaths (She J, et al. Chest. 2013, 143(4): 1117-1126). Breast cancer is the most common cancer among women worldwide currently facing, with about 1,380,000 new cases of breast cancer diagnosed and 458,000 deaths each year. According to reports, 232,340 new cases of breast cancer in the United States were diagnosed each year. In 2011, in the United States, nearly 40,000 women died from breast cancer; in India, 100,000 new cases of breast cancer were diagnosed each year, and one in 28 women developed to breast cancer (Yadav D K, et al. Curr. Med. Chem. 2014, 21(9): 1160-1170); in China, breast cancer has also become the most common cancer among women, with a total of 169,452 new cases of breast cancer diagnosed and 449,08 cases deaths until 2008, accounting for 12.2% and 9.6% of the world total, respectively. The total number of breast cancer cases diagnosed in China was half of those in Europe (332,000 cases in the overall population of 498 million in 2008), and roughly the same as in the United States (182,000 cases in the overall population of 304 million in 2008). If the trend remains constant, in China, breast cancer patients will be as high as 2,500,000 by 2021, with incidence rates increasing from less than 60 cases per 100,000 females (between the age of 55 and 69) to more than 100 cases per 100,000 females (Fan L, et al. Lancet Oncol. 2014, 15: e279-289). Globally, the number of women suffering from breast cancer is increasing, which poses a great threat to the survival of women. Colon cancer and rectal cancer are collectively called the colorectal cancer, which is a common malignant tumor of digestive tract, with incidence rates increasing an average of 2% per year, ranking second in cancer mortality in Europe and the United States, and ranking third in both incidence and mortality from cancer in the United State in 2003 (Xu, Fu Xing. International Journal of Digestive Diseases 2006, 26 (6): 365-366). In recent years, the incidence of colorectal cancer in China has risen dramatically, on a national scale, to the fourth in malignant tumor, and has ranked second in some fast-growing cities such as Shanghai (Li, De Lu, et al. Chinese Journal of Cancer. 2011, 20 (6): 413-418).
However, because most cancers are found in their medium or late stages, overall effects of clinical treatment are poor, and especially multidrug resistance continues to emerge, which makes the treatment of cancer difficult. Therefore, we must develop new anticancer drugs with high activities and low side effects to meet clinical needs.
Ferrocene, synthesized by Kealy and Pauson in 1951, has a unique sandwich structure with the divalent iron ions located between two plane rings being in a staggered conformation. Along with constantly deepening of research, various structure of ferrocene derivatives have been synthesized at home and abroad. Particularly in the field of pharmaceutical chemistry, the ferrocene derivatives show more pronounced activities: E. I. Edwards, et al. introduced ferrocenyl moieties into penicillin and cephalosporin, resulting in greatly improving the bactericidal activity (E I Edwards, et al. J. Organomet. Chem. 1975, 85: C23); the research done by A. R. Tajcrak, et al. showed that the ferrocene derivatives have insecticidal activity; the research done by A. Rosenefeld, et al. showed that the ferrocene-modified cisplatin derivatives have very strong inhibitory activity against leukemia, and the nephrotoxic is much lower than cis-DDP (A. Rosenfeld, et al. Inorg. Chim. Acta. 1992, 201:219); the research done by E. I. Klimova, et al. showed that the cyclopropane-containing ferrocene derivatives have strong anti-inflammatory activity (E. I. Klimova, et al. J. Organomet. Chem. 2012, 708-709: 37-45); X. F. Huang et al. synthesized a series of ferrocene derivatives containing pyrazole rings, and the activity studies showed that some of the compounds have stronger anticancer activities than 5-fluorouracil (X. F. Huang, et al. J. Organomet. Chem. 2012, 706-707: 113-123); W. Liu et al. synthesized a series of ferrocene derivatives containing urea, and the activity studies showed that some compounds have strong inhibition activity against HIV-1 protease (W. Liu, et al. Appl. Organomet. Chem. 2012, 26: 189-193); ferrocene-quinoline derivatives
(FQ, SSR97193) have strong antimalarial activity, and have entered phase II clinical research.
U.S. patent application No. 8426462B2 disclosed that the ferrocene derivatives containing aromatic rings have strong inhibitory activity against human breast cancer cell line MDA-MB-231 and prostate cancer cell line PC-3.
In recent years, our research team has been devoted to the study of the design, synthesis and anticancer activity studies of small-molecule anticancer drugs. Ferrocene is a lead compound for the design and synthesis of antitumor drugs (E. W. Neuse. J. Inorg. Organomet. P. 2005, 15(1):3-32; S. S. Braga, et al. Organometallics, 2013, 32: 5626-5639). In our previous work, we designed and synthesized a series of novel structure ferrocene-carboxylic acid derivatives, studied their initial anticancer activities, and the results showed that most of the compounds have stronger anticancer activity than the positive controlling drug Gefitinib (Yong, Jianping, et al. Application Publication No. CN103601762A). Based on the good results achieved in our patent application publication No. CN103601762A, we continue to design and synthesize ferrocene derivatives with novel structures to find lead compounds or candidate compounds for clinical use.